Novel prolinamide-supported polystyrene as highly stereoselective and recyclable organocatalyst for the aldol reaction

Article abstract of DOI:10.1002/adsc.200800090

A new prolinamide derivative anchored to a polystyrene support has been straightforwardly prepared and employed as heterogeneous catalyst in the direct asymmetric aldol reaction with good results in terms of yield and stereoselectivity. The optimal reacti

Full text of DOI:10.1002/adsc.200800090

FULL PAPERS
DOI: 10.1002/adsc.200800090
Novel Prolinamide-Supported Polystyrene as Highly
Stereoselective and Recyclable Organocatalyst for the Aldol
Reaction
Michelangelo Gruttadauria,a,* Francesco Giacalone,a
Adriana Mossuto Marculescu,a and Renato Notoa
a
Dipartimento di Chimica Organica “E. Paternò”, Università di Palermo, Viale delle Scienze, Pad. 17, 90128 Palermo, Italy
Fax : (+39)-091-596-825; e-mail: mgrutt@unipa.it
Received: February 11, 2008; Revised: March 6, 2008; Published online: May 16, 2008
Dedicated to the memory of Prof. G. C. Cusmano.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A new prolinamide derivative anchored to water. Noticeably, the enantioselectivities obtained
a polystyrene support has been straightforwardly employing acetone as ketone were, to the best of our
prepared and employed as heterogeneous catalyst in knowledge, the highest achieved with a supported
the direct asymmetric aldol reaction with good re- proline derivative. This catalyst can be easily recov-
sults in terms of yield and stereoselectivity. The opti- ered, regenerated and recycled, without loss of activ-
mal reaction conditions were found when a 1:2 (v/v) ity, at least for twelve cycles.
water/chloroform mixture was used. This mixture
was the best compromise between the good swelling
properties of chloroform and the formation of a con- Keywords: aldol reactions; immoblization; organic
centrated organic phase due to the presence of catalysis; polymers; proline
Introduction
inexpensive and available in both enantiomeric forms.
However, immobilization of l-proline has allowed
Asymmetric organocatalysis, especially with l-proline one to reach, in several cases,[4b,d,f] higher stereoselec-
and its derivatives, has experienced a huge interest tivities compared to the native catalyst. Immobiliza-
and development in the recent years.[1] In fact, l-pro- tion of more expensive organocatalysts, such as substi-
line and several its derivatives have emerged as pow- tuted prolinamides, may be of higher interest from an
erful catalysts in the asymmetric intermolecular aldol economical point of view. Substituted prolinamides
reaction, one of the most important methods of form- have been recently found to be active and highly ste-
ing carbon-carbon bonds.
reoselective catalysts for direct aldol reaction in aque-
On the other hand, since the organocatalyst is usu- ous medium.[9] Indeed, since 2006, when Barbas[10]
ally used in a substantial quantity, in some cases up to and Hayashi[11] independently reported the highly ste-
30 mol%, its recovery and reuse became fundamental reoselective aldol reactions using proline derivatives
in order to reduce costs and to facilitate the separa- as organocatalysts in the presence of water,[12] this
tion of the products, especially when the catalyst is point has received attention.[13] Particularly, com-
obtained after several synthetic steps.[2] Immobiliza- pound 1 (Figure 1) gave excellent results in the direct
tion of organocatalyst to the support can be realized aldol reaction.[9a]
both with a non-covalent linkage[3] or with a covalent
linkage on supports such as polystyrene,[4] silica,[5]
PEG,[6] magnetite[7] or ionic liquids.[8] Recently, the
immobilization of l-proline on polystyrene has re-
ceived interest, and indeed stereoselective and recy-
clable materials have been prepared.[4] Immobilization
of l-proline may be considered useless since proline is Figure 1. Prolinamide catalyst for direct aldol reactions.
Adv. Synth. Catal. 2008, 350, 1397 – 1405
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Interestingly, there are no reports in the literature been removed under smooth conditions by using
about the use of immobilized organocatalysts giving formic acid. This procedure gave the supported-
high ee values (>90%) in the reaction between ace- prolinamide resin 2 in high yield with a prolinamide
tone and substituted benzaldehydes. We considered it loading of ca. 0.74 mmolgÀ1, as determined by ele-
possible to obtain high ee values for the above reac- mental analysis and weight gain.
tion using an immobilized organocatalyst. We coupled
Once the catalyst was prepared, we focused our at-
the idea of using compound 1 with our immobilization tention on the aldol reaction between two ketones
procedure with the aim to obtain a recyclable catalyst. (acetone and cyclohexanone) and 4-nitrobenzalde-
Our intention was to prepare a recyclable supported hyde (Table 1). First, we tried to determine the best
version of 1 while trying to maintain its excellent be- solvent system and, in the mean time, recycling stud-
haviour. Here, we report the results of the direct ies were performed. Indeed, because one of the most
asymmetric aldol reaction between several ketones important features of a supported catalyst should be
and substituted benzaldehydes catalyzed by a substi- its high reusability, we decided to carry out recycling
tuted prolinamide anchored to a polystyrene resin.
experiments at the beginning of our study in order to
find the best conditions for catalyst reuse for further
applications. As a first approach we studied the reac-
tion between acetone and 4-nitrobenzaldehyde using
brine, water and CHCl3 (Table 1, entries 1–3) in order
Results and Discussion
Resin 2 has been prepared by following a straightfor- to compare these different reaction media. Using
ward synthetic strategy in two steps, as depicted in brine we were able to reproduce the ee value ob-
Scheme 1. Firstly, l-Pro derivative 3[4b] has been react- tained under homogeneous conditions, however, the
ed with commercial (2S)-2-amino-1,1,2-triphenyletha- yield was modest. No differences were observed using
nol (4) in the presence of ethyl chloroformate[14] to water. The reaction carried out in CHCl3 afforded the
afford the corresponding prolinamide derivative 5. product in a very low yield (entry 3). Reuse of cata-
Secondly, due to the presence of a styrenic moiety in lyst in brine gave a decreased yield (Table 1, entry 4)
its structure, 5 can be promptly linked to a commer- although the ee value was unaffected. We reasoned
cially available mercaptomethyl-functionalized poly- that a certain amount of catalyst was probably disacti-
styrene (1% cross-linked with DVB, spherical beads, vated by an excess of acetone with formation of the
particle size 100–200 mesh) via a radical reaction in corresponding imidazolidinone.[15] Therefore, we de-
the presence of AIBN. Finally, the Boc group has cided to regenerate the catalyst by treatment with
formic acid in order to hydrolyze the imidazolidi-
none.[16] Interestingly, a beneficial effect was observed
after regeneration of the resin because we obtained
again the same yield as displayed by fresh catalyst
(entries 1 and 5). However, such a yield was still dis-
appointing. Because we were interested both in high
yield and ee values and high recyclability of the cata-
lyst, new regenerations were carried out after each
cycle. Contrasting effects were obtained in terms of
enantioselectivity when no solvent was used and a
negative effect of dilution was observed when
10 equiv. of acetone were used (entries 6 and 7). Then
we decided to try a 1:2 (v/v) water/chloroform mix-
ture. To our delight, excellent results were achieved
by adopting this solvent system. In fact, both yields
and enantioselectivities were boosted to 96 and 95%,
respectively (entry 8). It is worthy to note that such
an ee value was higher than that obtained with 1
under homogeneous conditions. The reaction per-
formed at À58C gave an improved enantioselectivity
but, a dramatic drop in activity was observed
(entry 9). Use of other solvents such as CH2Cl2, tetra-
hydrofuran, toluene and diethyl ether gave very low
yields (entries 10–13) while the reaction took place,
with high ee values, when the above solvents were
used as a 1:2 (v/v) water/solvent mixture (entries 14–
Scheme 1. Synthesis of polystyrene-supported prolinamide.
17).
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Table 1. Asymmetric aldol reactions in water between acetone or cyclohexanone and 4-nitrobenzaldehyde catalyzed by resin
2 (10 mol%).
Entry
Ketone
Solvent
Cycle
Regeneration[a]
Yield[b] [%]
anti/syn[c]
ee[d]
1[e]
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
brine
H2O
CHCl3
brine
brine
none
acetone
H2O/CHCl3
H2O/CHCl3
CH2Cl2
THF
toluene
1
1
1
2
3
3
4
4
4
1
1
1
1
2
2
2
2
1
2
3
4
5
6
7
8
9
10
11
12
-
-
-
-
1
2
3
3
3
-
-
-
-
1
1
1
1
-
-
-
-
-
1
1
2
3
4
5
6
41
42
5
30
42
34
12
96
13
5
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
85
85
nd
85
86
94
86
95
98
nd
nd
nd
nd
96
92
94
92
95
97
-
86
50
97
97
97
97
97
97
97
2[f]
3[g]
4[e]
5[e]
6
7[h]
8[i]
9[i,j]
10[g]
11[g]
12[g]
13[g]
14[i]
15[i]
16[i]
17[i]
18[f]
19[i]
20[g]
21[k]
22[i]
23[i]
24[i]
25[i,l]
26[i]
27[i]
28[i]
29[i]
<5
7
7
Et2O
H2O/CH2Cl2
H2O/THF
H2O/toluene
H2O/Et2O
H2O
80
44
50
37
50
97
-
36
46
91
51
83
97
97
97
95
acetone
-
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
94/6
95/5
-
H2O/CHCl3
CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
H2O/CHCl3
95/5
97/3
94/6
93/7
98/2
96/4
96/4
96/4
96/4
[a]
Regeneration with formic acid during 2.5 h.
Isolated yield.
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
Using 500 mL of brine.
Using 300 mL of H2O.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
1
Using 300 mL of solvent.
No solvent and 5 mmol (10 equiv.) of acetone were used.
Using 100/200 mL of H2O/solvent.
Reaction carried out at À58C.
[j]
[k]
[l]
Using 50/250 mL, respectively.
Resin treated with formic acid during 1.5 h.
Then, we checked the aldol reaction of cyclohexa- to the 1:2 (v/v) water/chloroform mixture. To our de-
none with 4-nitrobenzaldehyde and, in the mean time, light, this solvent system again worked nicely with
other recycling studies were also performed (Table 1). almost quantitative yield and high stereoselectivity
Following the results obtained using acetone, we (entry 19). Then, we observed that when water was
used again water, chloroform and 1:2 (v/v) water/ absent or present in a minor amount, the reaction did
chloroform as reaction medium. Although water not take place or proceeded with bad results (en-
seemed to work, giving high stereoselectivity, the con- tries 20 and 21) demonstrating that again water
version was low (entry 18). We turned our attention played a crucial role. In the fifth cycle (entry 22) we
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Michelangelo Gruttadauria et al.
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used same conditions as in entry 19, but both yield
and stereoselectivity were lost. Then, we regenerated
the resin by treatment with formic acid. Again, the
resin worked almost as well as in the second cycle
(see entries 23 and 19). A new reaction was per-
formed without regeneration and once again conver-
sion fell down (entry 24). Then, new regenerations
were carried out after each cycle, and the resin always
showed the same activity (entries 25–29). As can be
seen from the data reported, the optimal solvent
system was a CHCl3/H2O mixture. In our opinion this
is a result of a synergistic effect of the two solvents.
Chloroform should be able to swell the hydrophobic
prolinamide catalyst. However, no reaction took
place when only CHCl3 was used simply because it is
a good solvent. Ketones and aldehydes are well dis-
solved, while the catalytic center is supported on a
material having a very low surface area (<10 m2 gÀ1).
This strongly favors the repartition of the reactants in
the liquid phase. Using water, reactions occurred in a
concentrated organic phase, so a higher conversion
with respect to CHCl3 was observed, but it was not
high because the presence of the bulky hydrophobic
moieties on the prolinamide catalyst did not allow an
open structure of the catalyst in water (see Figure 2).
The water/chloroform mixture was the optimal system
because CHCl3 allowed the catalyst to adopt an open
structure while water created a concentrated organic
phase as depicted in Figure 3. In other words, the
above mixture was a good compromise between swel-
ling and formation of a concentrated organic phase. A
similar behavior was observed when CH2Cl2, tetrahy-
drofuran, Et2O or toluene were employed. Interest-
ingly, when the above solvents were used as mixture
with water, yields decreased in the order CHCl3 >
CH2Cl2 >toluene>THF>Et2O. This order is in
agreement with the swelling studies carried out on
DVB cross-linked polystyrene resins.[17]
Figure 2. Proposed unswelled catalyst structure in the pres-
ence of water.
Next we carried out aldol reactions using a set of
substituted benzaldehydes. In Table 2 the results ob-
Figure 3. Proposed swelled catalyst structure in the presence
tained using acetone as donor are reported. Adopting of chloroform/water mixture.
the optimal conditions, activated aldehydes showed
good to excellent results both in terms of conversion
and enantiomeric ratio, being the latter in the 89– action between acetone and 4-nitrobenzaldehyde.
97% range. In some cases, ca. 3–9% of the corre- Catalyst 2 was used up to 11 cycles, regenerating it
sponding a,b-unsaturated compounds were observed. after each cycle, without any loss in activity or selec-
Although under homogeneous conditions the yields tivity.
were 70–85% and ee values were 84–>99% in the
Next, a representative selection of aldehydes was
case of 4-CF3-benzaldehyde, with 4-NO2-benzalde- examined under the optimized conditions using cyclo-
hyde and 2-naphthaldehyde we observed higher ee hexanone as ketone and the results obtained are sum-
values. Improvements in the yields were achieved marized in Table 3.
both with longer reaction times (compare entries 2
Interestingly, aromatic aldehydes gave excellent re-
and 13) or by using 30 mol% of catalyst (compare en- sults, with reaction times ranging between 22 and
tries 6 and 12). The use of a larger amount of catalyst 120 h. Diastereoselectivities (anti/syn) and enantiose-
can be justified by the high recyclability of the cata- lectivities were excellent in all cases and low yields
lyst. As can be seen from Table 2, reactions were car- were observed only for less reactive aldehydes (en-
ried out with catalyst 2 previously employed in the re- tries 1, 10 and 12). It is worth mentioning that, since
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Novel Prolinamide-Supported Polystyrene
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Table 2. Aldol reaction of acetone with substituted benzaldehydes catalyzed by resin 2.
Entry
Ar
Time [h]
Cycle
Regeneration[a]
Yield[b] [%]
ee[c]
1
2
3
4
5
6
7
8
4-CN-C6H4
4-CF3-C6H4
3-Cl-C6H4
4-Cl-C6H4
Ph
2-naphthyl
2-Cl-C6H4
3-MeO-C6H4
4-Br-C6H4
2-CN-C6H4
2-Cl-6-NO2-C6H3
2-naphthyl
4-CF3-C6H4
22
24
48
72
93
95
67
96
72
24
24
95
48
5
5
5
6
6
6
7
8
4
4
4
5
5
5
6
7
8
9
9
10
10
93
58
79
67
50
30
94
57
67
95
98
44
74
96
95
94
93
92
90
89
91
97
93
96
92
95
9
9
10
11
12[d]
13
10
10
11
11
[a]
Regeneration with formic acid during 2.5 h.
Isolated yield.
Determined by HPLC using a chiral stationary phase.
We employed 30 mol% of catalyst.
[b]
[c]
[d]
Table 3. Asymmetric aldol reactions in water between cyclohexanone and aldehydes catalyzed by resin 2 (10 mol%).
Entry
R
Time [h]
Cycle
Regeneration[a]
Yield[b] [%]
anti/syn[c]
ee anti[d]
1
Ph
Ph
48
48
72
90
22
120
48
48
96
96
72
120
72
96
1
1
1
2
3
4
5
6
7
8
9
9
10
11
-
-
-
35
37
91
52
95
-
84
93
55
26
38
4
97/3
98/2
97/3
98/2
96.5/3.5
-
97.5/2.5
96/4
98/2
97/3
98/2
97/3
98/2
98/2
96
96
97
95
98
-
99
97
97
94
96
nd
96
96
2[e]
3
3-Cl-C6H4
2-naphthyl
4-CN-C6H4
cyclohexyl
4-CF3-C6H4
3-NO2-C6H4
3-CH3O-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-CH3O-C6H4
4-Cl-C6H4
4-CH3-C6H4
4
5
6
7
8
9
10
11
12
13[f]
14[f]
1
2
3
4
5
6
7
8
8
9
10
74
37
[a]
Regeneration with formic acid during 2.5 h.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
Determined by H NMR of the crude product.
Determined by HPLC using a chiral stationary phase.
Using 100 mL of brine instead of water.
We employed 30 mol% of catalyst.
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Table 4. Asymmetric aldol reactions in water between ketones and 4-nitrobenzaldehyde catalyzed by resin 2.
Entry
X
Time [h]
Cycle
Regeneration[a]
Yield[b] [%]
anti/syn[c]
ee anti[d]
1
-
22
22
22
22
48
22
48
2
2
2
3
4
7
8
1
1
1
2
3
6
7
44
80
94
90
60
59
54
41/59
97/3
98/2
98/2
96/4
98/2
97/3
71
98
95
95
98
93
96
2
CH2
O
O
3[e]
4
5
6
7
S
NBoc
CHCH3
[a-d]
As for Table 3.
5 equivalents of ketone used.
[e]
the catalyst proved to be highly recyclable, resin 2 can Conclusions
be used in a higher amount with the less reactive al-
dehydes. We used 2 in 30 mol% with 4-chlorobenzal- In summary, we have prepared a new, efficient, heter-
dehyde and 4-methylbenzaldehyde (entries 13 and ogeneous organocatalyst by employing a rapid and
14). Yields were improved and the higher amount of straightforward synthetic strategy. Such a prolina-
catalyst used did not negatively affect the anti/syn mide-supported polystyrene successfully worked in
ratio and enantioselectivity.[18]
the asymmetric direct aldol reaction using both cyclic
Moreover, if compared with our previously report- and acyclic ketones and various aryl aldehydes. The
ed proline-supported resin,[4b] catalyst 2 proved to be optimal reaction conditions were found when a 1:2
more active in the aldol reaction between cyclohexa- (v/v) water/chloroform mixture was used. This mix-
none and aromatic aldehydes. In fact, almost all the ture was the best compromise between the good
values of yield, diastereo- and enantioselectivities swelling properties of chloroform and the formation
were improved. Noticeably, even if compared with re- of a concentrated organic phase due to the presence
sults obtained under homogeneous conditions,[9a] in of water. The performances obtained in some cases
some case resin 2 showed some better results (i.e., en- improved the values observed under homogeneous
tries 8, 26–29 Table 1, entries 5, 7 and 11 Table 3). conditions or with a proline-based polystyrene. Partic-
Again, reactions were performed with recovered and ularly, the enantioselectivities obtained employing
regenerated catalyst.
acetone as ketone were, to the best of our knowledge,
To increase the scope of the methodology, the aldol the highest achieved with a supported proline-deriva-
reaction was extended to other ketones with 4-nitro- tive. It is worthy to note that our catalyst worked
benzaldehyde, and the results are summarized in nicely at room temperature while the excellent results
Table 4. Cyclopentanone gave
a
modest result displayed by prolinamide 1 under homogeneous con-
(Table 4, entry 1). Due to the higher cost of tetrahy- dition were obtained on carrying out the reactions at
dro-4H-pyran-4-one and tetrahydro-4H-thiopyran-4- À5 or À108C. Finally, although resin 2 needed a
one with respect to commercial aliphatic cyclic ke- simple regeneration treatment, that may be consid-
tones, we performed the reactions with a lower excess ered as a drawback, its high recyclability, at least for
of ketone (1.5 equiv. vs. 5 equiv.). Surprisingly, even twelve cycles, counterbalanced this aspect and makes
under such conditions the reactions worked pretty resin 2 a promising catalyst.
well, with the same stereoselectivity and only with
slight differences in terms of yields (compare: en-
tries 3 and 4 in Table 4, entry 2 in Table 4 with
Experimental Section
entry 19 in Table 1). Once again, catalyst 2 showed
enhanced activity in comparison with the proline-sup-
ported resin.
General Methods
NMR spectra were recorded with a Bruker 300 MHz spec-
trometer in CDCl3 as solvent. Solid-state 13C MAS NMR
spectra were recorded with a Bruker AV 400, 400 MHz
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Novel Prolinamide-Supported Polystyrene
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spectrometer with samples packed in zirconia rotors spin-
ning at 5 kHz. FT-IR spectra were recorded with a Shimad-
zu FTIR 8300 infrared spectrophotometer. Carbon and ni-
trogen contents were determined by combustion analysis in
a Fisons EA 1108 elemental analyzer. Optical rotations
were measured in chloroform with a Jasco P1010 polarime-
ter. Chiral HPLC analyses were performed with a Shimadzu
LC-10AD apparatus equipped with an SPD-M10 A UV de-
tector and Daicel columns (OD-H, AD-H, AS-H, 4.6 mm ”
250 mm) with hexane/isopropyl alcohol as eluent. Aldol
products, except (2S,1’R)-2-(hydroxy-(3-methoxyphenyl)me-
thyl)cyclohexan-1-one, (4R)-(2-cyanophenyl)-4-hydroxy-2-
butanone and (4R)-(2-chloro-6-nitrophenyl)-4-hydroxy-2-bu-
tanone are known compounds and showed spectroscopic
and analytical data in agreement with their structures.[9a,f,19]
resin was washed with a saturated solution of NaHCO3,
water, methanol and diethyl ether. The resin was dried in an
oven at 608C for several minutes (629 mg). The weight dif-
ference corresponds to the amount of Boc removed, which
is identical to the amount of available proline (0.47 mmol/
0.629 g=0.74 mmolgÀ1).
A
an-1-one: Oil; [a]D23: +7.9 (c 0.982, CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.20–1.34 (m, 1H), 1.50–1.81 (m,
4H), 2.03–2.10 (m, 1H), 2.28–2.35 (m, 1H), 2.37–2.50 (m,
1H), 2.55–2.64 (m, 1H), 3.80 (s, 3H), 3.96 (d, J=2.1 Hz,
1H, OH), 4.75 (d, J=8.7 Hz, 1H), 6.80–6.89 (m, 3H), 7.21–
7.26 (m, 1H); 13C NMR (300 MHz, CDCl3): d=24.7, 27.8,
30.8, 42.6, 55.2, 57.3, 74.6, 112.4, 113.3, 119.5, 129.3, 142.5,
˜
159.6, 215.5; IR (liquid film): nmax =3498, 1694, 1601,
1
1586 cmÀ1. The optical purity was determined by HPLC on
The anti/syn ratios were determined from the H NMR spec-
tra of the crude reaction mixtures. The ee values were deter-
mined from HPLC traces of the crude reaction mixtures.
a Chiralpak AS-H column [n-hexane/2-propanol, 90:10];
flow rate 1.0 mLminÀ1; tR
N
N
20.6 min. Anal. calcd. for C14H18O3: C 71.77, H 7.74; found:
C 71.68, H, 7.78.
A
(4R)-(2-Cyanophenyl)-4-hydroxy-2-butanone: Oil; [a]2D3:
1,2,2-triphenylethyl]-4-(4-vinylbenzyloxy)pyrrolidine-
2-carboxamide (5)
1
+96.2 (c 1.38, CHCl3); H NMR (300 MHz, CDCl3): d=2.10
(s, 3H), 2.72 (dd. J=17.7 and 9.6 Hz, 1H), 2.90 (dd. J=17.7
and 2.7 Hz, 1H), 3.90 (br s, 1H, OH), 5.40 (dd. J=9.6 and
2.6 Hz, 1H), 7.30 (dt, J=7.6 and 1.1 Hz, 1H), 7.52–7.57 (m,
2H), 7.63 (d J=7.6 Hz, 1H); 13C NMR (300 MHz, CDCl3):
d=30.9, 51.1, 68.1, 109.9, 117.7, 126.9, 128.3, 133.1, 133.7,
Triethylamine (776 mL, 5.51 mmol) was slowly added to a so-
lution of acid 3 (1.915 g, 5.51 mmol) in CH2Cl2 (18 mL) at
08C. Ethyl chloroformate (536 mL, 5.51 mmol) was added
dropwise and the solution was stirred at the same tempera-
ture for 15 min. Then, amino alcohol (1.414 g, 4.74 mmol)
was added and the resulting solution was stirred for 5 h. The
solution was diluted with some CH2Cl2. After filtration, the
solvent was removed under reduced pressure and the resi-
due was purified by column chromatography (petroleum
ether/ethyl acetate, 5/1–2/1); yield: 62%; mp 183–1858C;
146.7, 208.9; IR (liquid film): nmax =3434, 2223, 1714 cmÀ1.
˜
The optical purity was determined by HPLC on a Chiralpak
OD-H column [n-hexane/2-propanol, 95:5]; flow rate
1.0 mLminÀ1
;
tR
G
N
Anal. calcd. for C11H11NO2: C 69.83, H 5.86; found: C 69.91,
H 5.90.
[a]2D8: À159.8 (c 0.79, CHCl3). H NMR (300 MHz, CDCl3):
(4R)-(2-chloro-6-nitrophenyl)-4-hydroxy-2-butanone:
White solid; mp 122–1248C; [a]2D4: 414.5 (c 0.73, CHCl3);
1H NMR (300 MHz, CDCl3): d=2.17 (s, 3H), 2.84 (dd, J=
18.2 and 1.9 Hz, 1H), 3.31 (dd, J=18.2 and 10.4 Hz, 1H),
3.46 (br s, 1H, OH), 5.63 (dd, J=10.4 and 1.8 Hz, 1H), 7.26
(dd, J=8.0 and 8.0 Hz, 1H), 7.36 (dd, J=8.0 and 1.1 Hz,
1H), 7.45 (dd, J=8.0 and 1.2 Hz, 1H); 13C NMR (300 MHz,
CDCl3): d=30.8, 48.4, 67.0, 123.0, 129.3, 132.8, 133.4, 133.7,
d=1.08 and 1.41 (two singlets, rotamers, tert-butyl), 1.75–
1.81 (m, 1H, H-3, pyrrolidine ring), 2.26–2.33 (m, 1H, H-3,
pyrrolidine ring), 3.28–3.62 (m, 3H, OH, H-5 pyrrolidine
ring), 3.86–4.31 (m, 4H, H-2 and H-4 pyrrolidine ring,
OCH2Ph), 5.14 (d, J=11.1 Hz, CH=CH2), 5.63 (d, J=
17.4 Hz, CH=CH2), 5.90 (d, J=7.2 Hz, NH-CH), 6.63 (dd,
J=17.4 and 11.1 Hz, CH=CH2), 6.95–7.30 (m, 17H, ArH).
7.45–7.50 (m, 2H, ArH), 8.05 (d, J=7.2 Hz, NH-CH). IR
˜
151.7, 208.7; IR (nujol): nmax =3381, 1708, 1543 cmÀ1. The
˜
(nujol): nmax =3385, 1701, 1650 cmÀ1
optical purity was determined by HPLC on a Chiralpak
C39H42N2O5: C 75.70, H 6.84, N 4.53; found: C 75.61, H 6.78,
N 4.49.
AD-H column [n-hexane/2-propanol, 95:5]; flow rate
1.0 mLminÀ1
;
tR
N
E
Anal. calcd. for C10H10ClNO4: C 49.30, H 4.14, N 5.75;
found: C 49.36, H 4.19, N 5.80.
Polystyrene-Supported l-Prolinamide (2)
Mercaptomethylpolystyrene (385 mg, 0.962 mmol) was
added to a degassed solution of compound 5 (1.787 g,
2.888 mmol) and AIBN (9.5 mg, 0.057 mmol) in toluene
(23 mL). The mixture was stirred at 1108C overnight under
argon. After cooling to room temperature, the resin was fil-
tered and washed with dichloromethane. A brilliant yellow
resin was obtained; yield: 676 mg. From the weight increase
it was calculated that 0.47 mmol of monomer has been cova-
lently attached to the resin. The dichloromethane solution
was evaporated under reduced pressure in order to recover
the unreacted prolinamide 5 which was then purified by
column chromatography (recovery: 90%). The resin was
suspended in HCOOH (1.4 mL) and stirred for 20 h. After
this time, water was added and the mixture was filtered. The
Typical Procedure for Aldol Reaction
Catalyst 2 was added (0.05 mmol) to a mixture of the corre-
sponding aldehyde (0.5 mmol) and ketone (0.75 or
2.5 mmol) in distilled water (0.10 mL) and chloroform
(0.20 mL) and the reaction mixture was stirred at room tem-
perature. The reaction mixture was filtered, the catalyst was
washed thoroughly with methanol, ethyl acetate and diethyl
ether. The organic layers were collected and, after evapora-
tion of solvent, the crude product was checked by H NMR
spectroscopy and HPLC, and was then purified by chroma-
tography (petroleum ether/ethyl acetate).
1
Adv. Synth. Catal. 2008, 350, 1397 – 1405
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1403

Michelangelo Gruttadauria et al.
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Supporting Information
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